The present invention is directed to the field of ophthalmic anti-infective/anti-inflammatory compositions and associated methods of treatment in mammals, particularly humans. More specifically, the present invention is directed to new ocular anti-infective/anti-inflammatory compositions containing tobramycin and dexamethasone.
The use of tobramycin and dexamethasone in combination to treat ophthalmic infections and attendant inflammation is known. Similarly, the use of these compounds in combination to treat inflammation and prophylactically treat (i.e., prevent or ameliorate) infections, such as in conjunction with an ocular surgical procedure, is also known. A product of this type is marketed by Alcon Laboratories, Inc. in the United States and other countries as TOBRADEX® (tobramycin 0.3%/dexamethasone 0.1%) Ophthalmic Suspension. This product has been available in the United States since 1988. It has been widely accepted as being the state-of-the-art ophthalmic anti-infective/anti-inflammatory product for many years. Further details regarding the composition of TOBRADEX® brand ophthalmic suspension are provided in U.S. Pat. No. 5,149,694.
The present invention is directed to the provision of improved tobramycin/dexamethasone compositions for topical ocular application. In particular, the invention is directed to the provision of compositions that contain xanthan gum and have a pH in the range 5 to 6. The viscosities of the compositions at the time of manufacture and during storage in a container prior to use are considerably less than would normally be expected based on the concentrations of xanthan gum utilized. This lowering of the viscosity prior to use is advantageous relative to dispensing of the compositions from a dropper bottle (e.g., DROPTAINER™, Alcon Laboratories, Inc.) or other container when administering the compositions to a patient. The reduction of the viscosities of the compositions at the time of manufacture and during storage prior to application to the eye is attributable to ionic interactions between the tobramycin and xanthan gum which occur at a pH of 5 to 6. Those interactions, if left uncontrolled, lead to the formation of clumps of tobramycin and xanthan gum and/or precipitation of the xanthan gum. The present invention is based in part on the discovery of formulation components and parameters that have been shown to be effective in controlling the tobramycin/xanthan gum interactions.
As indicated above, the compositions of the present invention contain xanthan gum. The use of xanthan gum as a component of ophthalmic compositions is described in U.S. Pat. No. 4,136,177; U.S. Pat. No. 6,352,978; U.S. Pat. No. 6,174,524; and U.S. Pat. No. 6,261,547. The '978 patent describes the use of is xanthan gum in combination with tobramycin. It indicates that xanthan gum and tobramycin are incompatible at a pH of 5.0 to 7.8, and teaches that this incompatibility problem can be avoided by formulating tobramycin/xanthan gum compositions to have a pH in the range of 7.9 to 8.6. A product based on the invention described in the '978 patent is marketed by affiliates of Alcon Laboratories, Inc. in Europe and several other countries.
The '524 and '547 patents describe xanthan-based ophthalmic compositions formulated as non-gelled liquids that gel upon topical application to the eye. The compositions of the '524 and '547 patents are formulated so that their total ionic strength is approximately 120 mM or less, and preferably about 94 mM or less. The compositions of the '524 and '547 patents that have a total ionic strength greater than about 120 mM do not gel upon contact with the eye. The compositions of '524 and '547 patents are generally viscous and gel upon topical application to the eye. In contrast, the compositions of the present invention generally have lower viscosities in the bottle, but the viscosities increase significantly following application to the eye, as interactions between tobramycin and xanthan gum are broken down.
The tobramycin/dexamethasone compositions of the present invention are formulated at a pH of 5 to 6. This pH range is necessary in order to maintain the stability of dexamethasone. The use of a pH in this range for an ophthalmic tobramycin/dexamethasone composition is described in U.S. Pat. No. 5,149,694. TOBRADEX® (tobramycin 0.3%/dexamethasone 0.1%) Ophthalmic Suspension also has a pH in this range.
The present invention resulted from an effort to create improved tobramycin/dexamethasone formulations, particularly compositions that provide for enhanced bioavailability of tobramycin and/or dexamethasone upon topical application to the eye, via the use of xanthan gum as a vehicle for tobramycin and dexamethasone. However, as described above, it was discovered that ionic interactions between tobramycin and xanthan gum at a pH of 5 to 6 lead to clumping and/or precipitation of the xanthan gum. In addition, it was discovered that xanthan gum slowly undergoes deacetylation during storage, thereby resulting in a stability problem. As explained in greater detail below, the present invention is based on the discovery of solutions to these problems.